Therapeutic inhibitor of vascular smooth muscle cells

Abstract

Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent.

1. A method of maintaining vessel luminal area, comprising inserting into the mammalian vessel an intravascular stent comprising a cytostatic amount of a cytoskeletal inhibitor effective to inhibit or reduce stenosis or restenosis upon placement of the stent, wherein the cytoskeletal inhibitor is not staurosporin or colchicine, wherein the cytostatic amount of the cytoskeletal inhibitor is an amount of the cytoskeletal inhibitor that exerts minimal protein synthesis inhibition and cytotoxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells. 
     
     
       2. The method of  claim 1  wherein the intravascular stent comprises metal or plastic. 
     
     
       3. The method of  claim 1  wherein the intravascular stent comprises a biodegradable material. 
     
     
       4. The method of  claim 3  wherein the intravascular stent consists essentially of a biodegradable material. 
     
     
       5. The method of  claim 1  wherein the cytoskeletal inhibitor is in sustained release form. 
     
     
       6. The method of  claim 5  wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof. 
     
     
       7. The method of  claim 5  wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to vascular smooth muscle cells, stromal cells or interstitial matrix surrounding vascular smooth muscle cells. 
     
     
       8. The method of  claim 1  wherein the intravascular stent comprises a biodegradable coating or a porous non-biodegradable coating comprising the cytoskeletal inhibitor. 
     
     
       9. The method of  claim 1  wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof. 
     
     
       10. The method of  claim 1  wherein the vessel is subjected to further vascular trauma. 
     
     
       11. The method of  claim 1  wherein the vessel is subjected to angioplasty. 
     
     
       12. The method of  claim 9  wherein the cytochalasin is cytochalasin B or an analog thereof. 
     
     
       13. A method for maintaining vessel luminal area, comprising inserting into a mammalian vessel an intravascular stent comprising a matrix and a cytostatic amount of a cytochalasin or an analog thereof effective to inhibit or reduce stenosis or restenosis upon placement of the stent, wherein the cytostatic amount of the cytochalasin or an analog thereof is an amount of the cytochalasin or an analog thereof that exerts minimal protein synthesis inhibition and cytotoxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells. 
     
     
       14. The method of  claim 13  wherein the cytochalasin or analog thereof is in sustained release form. 
     
     
       15. The method of  claim 13  wherein the matrix of the stent is impregnated with the cytochalasin or analog thereof. 
     
     
       16. The method of  claim 15  wherein the intravascular stent further comprises a coating comprising an amount of an inhibitor of vascular smooth muscle cell proliferation. 
     
     
       17. The method of  claim 13  wherein the intravascular stent comprises a coating comprising the cytochalasin or analog thereof. 
     
     
       18. The method of  claim 17  wherein the matrix is impregnated with an amount of an inhibitor of vascular smooth muscle cell proliferation. 
     
     
       19. The method of  claim 13 ,  14 ,  15  or  17  wherein the cytochalasin comprises cytochalasin B. 
     
     
       20. A method for maintaining vessel luminal area, comprising inserting into a mammalian vessel an intravascular stent which comprises a matrix and a coating on said matrix, wherein the coating and the matrix together comprise a cytostatic amount of a cytoskeletal inhibitor effective to inhibit or reduce stenosis or restenosis upon placement of the intravascular stent, wherein the cytoskeletal inhibitor is not staurosporin or colchicine, wherein the cytoskeletal inhibitor is an amount of the cytoskeletal inhibitor that exerts minimal protein synthesis inhibition and toxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells. 
     
     
       21. The method of  claim 20  wherein the cytoskeletal inhibitor is in sustained release form. 
     
     
       22. The method of  claim 20  wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof. 
     
     
       23. The method of  claim 22  wherein the cytochalasin comprises cytochalasin B. 
     
     
       24. The method of  claim 14  or  21  wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to vascular smooth muscle cells, stromal cells or interstitial matrix surrounding vascular smooth muscle cells. 
     
     
       25. The method of  claim 16 ,  17 , or  19 , wherein the coating is formed form a biodegradable material. 
     
     
       26. The method of  claim 13  or  20  wherein the vessel is subjected to angioplasty prior to stent placement. 
     
     
       27. A method for maintaining vessel luminal area, comprising administering to a mammal a cytostatic amount of a cytoskeletal inhibitor effective to biologically stent said vessel, wherein the cytoskeletal inhibitor is administered in conjunction with intravascular stent placement, wherein the cytoskeletal inhibitor is not staurosporin or colchicine, wherein the cytostatic amount of the cytoskeletal inhibitor is an amount of the cytoskeletal inhibitor that exerts minimal protein synthesis inhibition and cytotoxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells. 
     
     
       28. The method of  claim 27 , wherein the cytostatic amount of the cytoskeletal inhibitor is effective to inhibit or reduce stenosis or restenosis following stent placement. 
     
     
       29. The method of  claim 27  wherein the cytostatic amount of the cytoskeletal inhibitor is effective to inhibit vascular smooth muscle cell proliferation.